In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis

Lutz, Werner

doi:10.1016/0165-1110(79)90006-x

Cited by 398 publications

(132 citation statements)

References 202 publications

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“…For instance, line 1 of Table I shows that after a dose of 2.6 · 10 6 dpm/kg body weight a specific activity of 89 • 10 6 dpm/kg DNA resulted. A similar accumulation can be observed with the methylation of liver DNA by dimethylnitrosamine [7] and is an indication of strong carcinogenicity of the compound under investigation.…”

Section: Resultssupporting

confidence: 76%

“…AFM 1 • The CBI for rat liver DNA has been shown to correlate semiquantitatively with the carcinogenic potency of a compound [7] 0 It was shown that a CBI of 10 3 -10 4 stands for strong hepatocarcinogens, a CBI of 10 2 for moderate, and of about ten for weak hepatocarcinogens. An extensive discussion [ 7] of the predictive value of a CBI revealed that a comparison of structurally related chemieals like AFB 1 and AF!\1t can very well be based quantitatively upon measurement of DNA bindingo…”

Section: Resultsmentioning

confidence: 99%

“…An extensive discussion [ 7] of the predictive value of a CBI revealed that a comparison of structurally related chemieals like AFB 1 and AF!\1t can very well be based quantitatively upon measurement of DNA bindingo…”

Section: Resultsmentioning

confidence: 99%

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In vivo covalent binding of aflatoxin B1 and aflatoxin M1 to liver DNA of rat, mouse and pig

Lutz

Jaggi

Lüthy

et al. 1980

Chemico-Biological Interactions

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Section: Resultssupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

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In vivo covalent binding of aflatoxin B1 and aflatoxin M1 to liver DNA of rat, mouse and pig

Lutz

Jaggi

Lüthy

et al. 1980

Chemico-Biological Interactions

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“…The TD 50 values were taken from Gold et al (1984) and were converted to molar units. CBI values for liver DNA were from the review by Lutz (1979) and from more recent original publications (see legend to Fig. 1 ).…”

Section: Carcinogenic Potency Of Mutagensmentioning

confidence: 99%

Quantitative evaluation of DNA binding data for risk estimation and for classification of direct and indirect carcinogens

Lutz

1986

J Cancer Res Clin Oncol

Self Cite

104

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Summary.Investigation of covalent DNA binding in vivo provided evidence for whether a test substance can be activated to metabolites able to reach and react with DNA in an intact organism. Fora comparison of DNA binding potencies of various compounds tested under different conditions, a normalization of the DNA lesion with respect to the dose is useful. A covalent binding index, CBI = (JliDol chemical bound per mol DNA nucleotide )/(mmol chemical administered per kg body weight) can be determined for each compound. Whether covalent DNA binding results in tumor formation is dependent upon additional factors specific to the cell type. Thus far, all compounds which bind covalently to liver DNA in vivo have also proven tobe carcinogenic in a long-term study, although the liver was not necessarily the target organ for tumor growth. With appropriate techniques, DNA binding can be determined in a dose range which may be many orders of magnitude below the dose Ievels required for significant tumor induction in a long-term bioassay. Rat liver DNA bindingwas proportional to the dose of aflatoxin B 1 afteroral administration of a dose between 100 J.Lgfkg and 1 ngfkg. The lowest dose was in the range of generat human daily exposures. Demonstration ofa Iack ofliver DNA binding (CBI<0

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“…After a single dose of 36 mg DENA/kg body weight, there will be about one 0 6 -ethylguanine per 10 5 DNA guanines, at a time between 6 and 12 h after oral administration (Scherer et al, 1977). A similar Ievel of RNA darnage can be expected (Lutz, 1979). A maximum rate of variant Tyr incorporation of 20/2 x 10-5 = 10-4 can be calculated from the two triplets coding for 20 Cys residues in MT.…”

Section: Discussionmentioning

confidence: 98%

Metallothionein protein variants generated in rat liver as a result of DNA and RNA ethylations by the carcinogen diethylnitrosamine

Jauch

Lutz

1986

Mutation Research/Environmental Mutagenesis and Related Subject

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SummaryMetallothionein (MT) is a protein which contains 20 cysteine residues but no aromatic amino acids. It was tested whether treatment of male rats with the hepatocarcinogen diethylnitrosamine (DENA) could ethylate nucleic acids in such a way that protein variants containing measurable amounts of aromatic amino acid residues could be isolated from the livers of treated animals. To give a low Iimit of detection, the "wrong" amino acid precursors were administered in radiolabelled form at high Ievels of activity (7 mCijkg each of [ 3 H]tyrosine and [ 3 H]phenylalanine). 11 p.Cijkg [ 14 C]cysteine was given as an intemal marker for MT biosynthesis. 6 h after amino acid administration, metallothionein (MT) was isolated from the liver and extensively purified. Afteracid hydrolysis and collection of Cys, Tyr, and Phe from an HPLC analysis of the amino acids, the 3 Hj 14 C ratio was determined. The carcinogen-treated rats exhibited a significantly higher ratio than the vehicle-treated animals. This type of in vivo assay might find interesting applications in the investigation of nucleic acid alkylations as promutagenic lesions.Since a !arge number of chemical carcinogens act by damaging DNA, many short-term screening tests for carcinogenicity are based upon the detection of mutational events. In the light of the recent findings that certain cellular proto-oncogenes can be activated by base Substitutions (refs. in Weinberg, 1985) the search for changes in amino acid composition of proteins could become a valuable tool.One majorproblern in proteinvariant analysis in non-clonal systems is the fact that minor changes in the relative abundance of the various amino acids in a small number of polypeptide * Present address:

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In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis

Cited by 398 publications

References 202 publications

In vivo covalent binding of aflatoxin B1 and aflatoxin M1 to liver DNA of rat, mouse and pig

In vivo covalent binding of aflatoxin B1 and aflatoxin M1 to liver DNA of rat, mouse and pig

Quantitative evaluation of DNA binding data for risk estimation and for classification of direct and indirect carcinogens

Metallothionein protein variants generated in rat liver as a result of DNA and RNA ethylations by the carcinogen diethylnitrosamine

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